In recent war-related conflicts, traumatic brain injury (TBI) has become a signature injury affecting a large percentage of the Veteran population. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for approximately 70-80% of all TBI among returning Veterans as well as the civilian population. Although most overt symptoms of mTBI resolve spontaneously within days or weeks of the injury, in 10-20% of mTBI victims some functional deficits persist, with recent estimates suggesting that as many as 44-50% of mTBI patients experience three or more symptoms at one-year post-injury. Repetitive mTBI is of particular interest because military personnel often have several mTBI exposures over the course of their lives and possibly within single deployments. Recurrent brain injuries, even when mild, may interfere with neuropsychological recovery. Repeated concussion has also been associated with chronic traumatic encephalopathy (CTE), a neurodegenerative disorder with progressive impairments of memory and cognition, as well as depression, anxiety, and motor abnormalities. Among the proposed environmental risk factors of neurodegenerative disease, TBI, including mild TBI, is probably one of the most consistent candidates for initiating the molecular cascades and provoking neurodegeneration leading to Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis. Consequently TBI has been shown to accelerate pathology and behavioral deficits in genetic models of AD or to enhance vulnerability to Parkinsonism-inducing neurotoxins. Recent evidence also identified TBI as an environmental risk factor of frontotemporal dementia (FTD), an early onset dementia associated in its behavioral variant with behavioral abnormalities, loss of sociability, or impulsive and irrational behavior. Our preliminary studies show that mild repetitive impacts to the head of mice using a controlled impactor (closed head injury) result in gliosis, white matter changes, and cognitive deficits 3 months after injury. Separately, we showed that macrophage colony-stimulating factor (CSF1), a key growth factor in the hematopoietic system, has prominent neuroprotective effects in acute brain injury when administered systemically after injury. These effects are mediated via CSF1 receptor (CSF1R) expressed at least in part by injured neurons. A newly discovered second ligand for this receptor, IL-34, seems to be equally or more potent than CSF1 in our model. Most importantly, for this proposal, preliminary studies show a remarkable recovery of memory impairment and reduced gliosis with a single bolus treatment of CSF1 after injury in our model of mTBI. Based on these preliminary data we hypothesize that mild traumatic insults to the central nervous system lead to long-term neurobehavioral deficits in mice which model in part the deficits observed in human mTBI patients, and that systemic treatment with CSF1 and IL-34 will attenuate brain injury and related behavioral deficits even if given days or weeks after injury. In this application we propose to refine our model of mTBI and assess long-term pathological and cognitive changes in wildtype mice. We will expose mice to multiple repetitive cortical impacts that are days or weeks apart and study the longterm consequences of these injuries. Most importantly, we will treat such impaired mice with neuroregenerative protein therapies days, weeks or months after the initial traumatic impact occurred. After completion of the proposed studies we expect to have preclinical proof for efficacy of CSF1 and/or IL-34 in reducing pathology and alleviating symptoms in mouse models of mTBI. Since CSF1 is used clinically in humans our findings may find rapid translation to the clinic.